Abstract: Traumatic brain injury (TBI) is the most common injury of the Iraq war, and with the increased use of improvised explosive devices, a majority of war-related brain injuries are closed head injuries that result from blast. The high incidence of stress-related psychiatric co-morbidities (in particular, PTSD and depression) in individuals with bTBI raises unique challenges for diagnosis. Mild TBI and stress-related psychiatric symptoms lead to similar clinical presentations as well as to similar cognitive neuropsychological impairments. The impact of overlapping neurologic and psychiatric conditions on neuropsychological and functional outcome remains unclear and a better understanding of their individual contributions and interactions is critical to the development of optimal intervention strategies for patients who suffered blast injury. Diffusion tensor imaging (DTI), a neuroimaging technique that measures the functional integrity of white matter, has proven to be especially sensitive to the subtle changes following mild non-blast TBI. Here we use DTI as a means of quantifying neural injury resulting from blast exposure and evaluate its utility in disentangling the contribution of mild bTBI and psychiatric co-morbidities to the constellation of cognitive and functional deficits seen in military personnel with blast injury. The specific goals of the proposed research are four-fold. First, this study aims to characterize the white matter abnormalities associated with mild bTBI, whether from primary blast or secondary/tertiary injury, and to evaluate whether there are regions in which diffusion abnormalities are unique diagnostic markers of TBI, and not of psychiatric symptoms. Second, this study aims to evaluate the functional significance of the observed microstructural white matter abnormalities. We hypothesize that performance in the domains of attention/executive function, memory, and psychomotor speed will be related to TBI-associated diffusion abnormalities, and that the relationship between cognitive performance and these white matter abnormalities will be moderated by the presence of psychiatric co-morbidities. Third, the study aims to uncover optimal predictors of cognitive functioning and quality of life following bTBI, taking into account that the contribution of bTBI-associated diffusion abnormalities and psychiatric co-morbidities may differ as a function of blast load and other injury-related variables. Finally, the study aims to examine how diffusion abnormalities and psychiatric co-morbidities are related to long-term cognitive and functional outcome, assessed at 9-month follow-up. This research has the potential not only to provide a sensitive diagnostic marker for neural changes associated with bTBI, but also to greatly enhance our understanding of the contributions of neural and psychiatric abnormalities to the cognitive and functional impairments associated with blast injury. PUBLIC HEALTH RELEVANCE: Complicating the diagnosis and treatment of individuals with blast-induced TBI (bTBI) is the high incidence of psychiatric co-morbidities, including PTSD and depression. Using diffusion tensor imaging, a method uniquely sensitive to the neural damage associated with TBI, this study aims to disentangle how neural abnormalities from bTBI and psychiatric symptoms contribute to a patient's clinical presentation. The study also seeks to examine the interrelationships among these factors and to develop optimal models of outcome prediction. Such information will enable clinicians to prioritize treatment and rehabilitation efforts, and will optimize the use of clinical resources. Through its theoretical and clinical contributions, this research will provide the foundation for better diagnosis and treatment of individuals with bTBI, and will foster the cognitive and psychosocial recovery of Service Members and their return to leading more productive family, community, and professional lives.